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11/30/2016
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Immune Cells and
Organs
Bonnie Hylander, Ph.D.
Dept. of Immunology
Oncology for Scientists
Dec 8, 2015
Immune system
Purpose/function?
• First line of defense= epithelial integrity=
skin, mucosal surfaces
• Defense against pathogens if skin broken
– Inside cells= kill the infected cell (Viruses)
– Systemic= kill- Bacteria, Fungi, Parasites
• Two phases of response
– Handle the acute infection, keep it from
spreading
– Prevent future infections
The Immune
System
The principal cellular
constituents, lymphocytes,
are mobile and continuously
recirculate between the
blood and the lymph by way
of the secondary lymphoid
tissues… where antigens
and antigen-presenting
cells are selectively
localized.”
-Masayuki, Nat Rev Immuno. May 2004
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Tolkien
Not all who wander are lost…..
Lord of the Rings
…..some are searching
Immune System
• Cells
– Innate response- several cell types
– Adaptive (specific) response- lymphocytes
• Organs
– Primary where lymphocytes develop/mature
– Secondary where mature lymphocytes and
antigen presenting cells interact to initiate a
specific immune response
• Circulatory system- blood
• Lymphatic system- lymph
Overview of the Immune System
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Cells= Leukocytes= white blood cells
Granulocytes
1. neutrophils
2. eosinophils
3. basophils
Non-granulocytes
4. monocytes
5. lymphocytes
Plasma (56%)
After centrifugation in
Ficoll, leukocytes are
found in the “buffy
coat” 1%
RBCs
Plasma- with anticoagulant
Serum- after coagulation
Where do all these cells come
from?
Hematopoeisis
Pleuripotent Hematopoeitic Stem Cells (HSC) • Give rise to second generation stem cells with
restricted lineage potential
Two lines of differentiation
• Myeloid lineage produces cells of innate system
(neutrophils, macrophages)
• Lymphoid lineage produces lymphocytes
Cells of the Immune System
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Granulocyte
lineage
“First Responders” HSC- Pleuripotent
Common
Myeloid
Progenitor
Eosinophil
Neutrophil
Basophil
(Myeloid = of or
relating to the bone
marrow)
Granulocytes
• Front line of attack during immune
response~ part of innate immune
response
• Identified by characteristic staining
patterns of “granules”
– Released in contact with pathogens
– Proteins with distinct functions: killing,
regulation of other cells, tissue remodeling
• All have multilobed nuclei
Neutrophils
• One of the main effector cells in the
innate immune system
• 50-70% of white blood cells
• Number of neutrophils increases during
infections~ “leukocytosis”~ diagnostic
• Kills microorganisms by phagocytosis
shown 100 years ago
• Main cellular component of pus
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Neutrophil
• Named based on staining
qualities of granules
• Multilobed nucleus=
polymorphonuclear
leukocyte= PMN
• Neutrophilic granules stain
lightly blue to pink
• 7-10 hrs in blood, then
migrates into tissues
• First responders- Motile &
phagocytic
• “Leukocytosis” indicates
infection
• Extracellular “traps”
http://www.youtube.com/watch?v=f
pOxgAU5fFQ
Extracellular Traps:
SEM of Staphylococcus
aureus bound to
neutrophil extracellular
traps (NETs).
• formed by activated
neutrophils
• can disarm and kill
bacteria
Stimulated neutrophil with NETs and some trapped Shigella (orange). Colored scanning electron micrograph.
Brinkman/Zychlinsky Nat Rev Micro 5: 2007
“Beneficial suicide: why neutrophils die to make
NETS”
Brinkmann: Max Planck Institute for Infection Biology
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Eosinophil
• Bilobed nuclei
• Motile, phagocytic
• Killing of antibody
coated parasites
• Degranulation of
substances that
kill parasites,
worms
Mast Cell
• Leave bone marrow as undifferentiated
cells and mature in tissues; histamine
• May be related to basophils (?)
Basophil
• <1% all leukocytes
• Non-phagocytic
• Nucleus obscured by
coarse blue (H&E)
granules
• Important in some
allergic responses
• Bind circulating Abs and
release histamine-
increasing permeability
of blood vessels
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Myeloid antigen presenting cells: Monocytes, macrophages, dendritic cells
• Phagocytic- uptake of antigens in
periphery
• Bridge between innate and adaptive
immune responses
• Digest proteins and present peptides in
MHC molecules on APC cell surface- Ags
recognized by lymphocyte receptors
• Interact with lymphocytes in lymph node
• Secrete proteins that attract and activate
other immune cells
Pleuripotent Stem Cell
Myeloid
lineage
Monocytes- macrophages & DCs
Monocyte
Monocyte
• Mononuclear (not lobed)
• Circulate in blood~ 8 hrs
• Bean-shaped nucleus
• Differentiate into macrophage after leaving the blood
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Macrophage (“big-eaters”)
• Monocytes enter tissues and become fully mature macrophages or dendritic cells
– Become phagocytic
• Free vs fixed tissue mΦ
– Special names in different organs- Kupffer cells- liver, osteoclasts- bone
• Surface receptors for Abs (opsinized Ags)
Dendritic cells
• Myeloid & lymphoid origins
• Best APC for presenting to naïve T-cells
• Ralph Steinman discovered them in mid 1970’s;
received Nobel Prize 2011
• Named for long processes; actively extend and
retract sampling Ags & examining T cells
• Ag capture in one place- then migrate- present
Ag in another place (eg. LN)
• Immature to mature; change in functionality from
phagocytic to migratory
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Dendritic cells
Source: National Cancer Institute (NCI) Sriram
Subramaniam
Hematopoesis (3) Pleuripotent Stem Cell
Myeloid
lineage
Platelets
Mega-
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Hematopoesis (4) Pleuripotent Stem Cell
Myeloid
lineage
Erythroid
Mature human and mouse RBCs have no nuclei
Salamander RBCs
HSC-
Lymphoid
lineage
Lymphocytes, NK
Adaptive Immune
Response
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Lymphocytes: 3 types
• 20-40% of WBC
• Cannot be distinguished morphologically
• T-cells
– helper CD4+ recognize Ag in context of MHCII on
APCs, secrete cytokines to tune immune response
– cytotoxic CD8+ recognize Ab in MHCI, kills cells
• B-cells
– become antibody producing plasma cells
• NK cells
– part of the innate immune response, kills cells lacking
MHC1
T and B
Lymphocytes
• Large nucleus with
chromatin that is
clumpy AND
smudgy
• Little cytoplasm
• Recognizes
specific Ags
• Responsible for
specificity and
memory of the
adaptive immune
response
Examples of lymphocytes:
Subsets
of Th
cells
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Ezra et al, J Global Inf dis 2010, Fig 1 (legend next slide)
Figure 1 :The immunology of resolving infection and disease
progression to Leishmania For both T helper 1 (TH1)- and TH2-cell
differentiations, antigens are presented to naive CD4+ T cells by
dendritic cells (DCs). The interaction of co-stimulatory molecules with
their respective ligands, together with the local cytokine environment,
promotes the differentiation of naive T cells into interferon- γ (IFN-γ)-
secreting TH1 cells or interleukin-4 (IL-4)-secreting TH2 cells. In TH1-
cell development, certain pathogens or pathogen-associated molecular
patterns (PAMPs) trigger antigen-presenting cells, through toll-like
receptors (TLRs), to secrete IL-12, which promotes the differentiation of
naive T cells into IFN-γ-secreting TH1 cells. In TH2-cell development, the
inability of antigen to activate DCs to produce IL-12 results in a default
pathway of naive T-cell differentiation into IL-4-secreting TH2 cells
CTL kill cells in 2 ways
Scientific American
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Condensed heterochromatin= resting
Decondensed chromatin= active
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Usually lives 1-2 weeks
Secretes 100’s- 1000 Ab molecules/sec
Figure 2.8e The Biology of Cancer (© Garland Science 2007)
Plasma cell
Perinuclear golgi
and abundant
layers of
endoplasmic
reticulum
Dendritic cells Macrophage B-cell
Antigen
Presenting Cells
3 kinds of cells
present Ag to T-
cells
Dendritic cells:
Professional APCs Several types
Capture, process,
present Ag
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Organs of Hematapoesis
change during development
Yolk Sac
•3 weeks
•Blood islands
•Erythro-myeloid stem
cells
•RBC’s are large and
nucleated=primitive
•Cannot form lymphoid
progeny
Fetal Liver
•5-6 weeks
•Seeded from
outside sources
•Max 6 mos then
declines to
neonatal stage
Bone Marrow
•Source of all stem
cells in adult
•B-cell maturation
•T-cells to thymus
•spleen
Organs of Hematopoesis
Fetal Liver
Hematopoetic colonies
Hepatocytes
Hematopoetic colonies
Adipose cells
Bone spicules
Bone Marrow
Organs of the
Immune
System
Thymus Bone Marrow
Stem cell
(in bone marrow)
1. Development &
maturation in primary
lymphoid organs
2. Distribution to
Secondary lymphoid
organs for engagement
with antigens
•Tonsils •Lymph nodes
•Spleen
•Peyer’s
Patches •Appendix
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• Outpocketing of cloaca day 4-5
• Day 11-12, nodules form from lining: cortex and medulla
Bursae
In birds, the Bursae of Fabricius is the site of B- cell maturation
Maturation of
T cells-
1. Hematopoesis/
development of myeloid
and lymphoid cells
2. Maturation of myeloid
and B-cells
• Lymphocytes arrive from yolk sac and
liver
• Epithelial cells remain connected via
desmosomes between their processes
forming a sponge-like meshwork of
epithelial cells= reticular epithelial cells
• Lymphocytes to proliferate and mature
• Mature, naïve T-cells leave and populate
secondary lymphoid organs
• If thymus fails to form, T-cells fail to
develop
The Thymus is the Site of T-cell Maturation
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Thymus Epithelial cell
Immature T-cells
(Thymocytes)
Hassal’s
corpuscle
Capillary
The cortex contains immature thymocytes which move
into the medulla as they mature.
Fetal Thymus: Lobes
Medulla- mature cells
Cortex- immature cells
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Thymus changes during life:
T-cell production
peaks during
puberty
Undergoes involution
T-cell production
reduced
Adult thymus undergoing involution loss of parenchyma; fatty infiltration
<Blue Histol>
Cortex
Adipose
Medulla
Nude mice
• Lack T-lymphocytes
• Recessive nude gene, chromosome 11
• Failure of thymic anlage to form
– no “home” for presumptive T-lymphocytes
• Hairlessness
• SCID mice are also immunodeficient but
for a different reason (failure of TCR, BCR
gene rearrangements and T&B cells do
not mature)
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DiGeorge syndrome
• deletion on chromosome 22
• defect of cranial neural crest cell
migration into arches
• congenital thymic hypoplasia= anlage of the thymus does not form
• variety of other defects involving facial,
thyroid, parathyroid and cardiovascular
system “Anlage”- an organ in its earliest stage of development; the foundation for subsequent
development, primordium
Scientists have grown a fully functional organ from transplanted
laboratory-created cells in a living animal for the first time.
• They grew a working thymus -- an important organ that supplies the
body with immune cells.
• Left: thymus epithelial cells were developed from MEF cells by
reprogramming.
• Right: transplanted to mouse kidney to form an organized and
functional mini-thymus in a living animal- sustained T-cell develop
Nicholas Bredenkamp, Svetlana Ulyanchenko, Kathy Emma O’Neill, Nancy Ruth Manley, Harsh Jayesh Vaidya, Catherine Clare Blackburn. An organized and functional thymus generated from FOXN1-
reprogrammed fibroblasts. Nature Cell Biology, 2014; DOI: 10.1038/ncb3023
Secondary lymphoid organs
• Specialized for trapping antigen
• Facilitates presentation to lymphocytes
• Characterized by:
– Localized areas for T-cells and B-cells
– Follicles where B cells mature
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Follicle with germinal center
Germinal Center Mantle
Zone: resting cells
(mantle zone lymphoma)
Light zone: more mature,
smaller centrocytes
contact follicular dendritic
cells
Dark zone: closely packed,
rapidly dividing
centroblasts
Lymphoid follicle
•Are formed when activated B cells
enter lymphoid follicles and proliferate – Somatic hypermutation
– Affinity maturation – Isotype switching of Ab class
•Selected B cells will mature to plasma
cells or become memory cells
Encapsulated peripheral lymphoid organs
• Lymph nodes-
– filter Ag from lymph
– Receive Ags and APCs from local sites
• Spleen-
– filters Ag from blood
– Ags from systemic infections
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The Lymph Node: filters lymph
• Interposed in the lymphatic vessels
• Present everywhere, but large and numerous ones are found in certain sites: – axillary, groin (inguinal LNs), near the
abdominal aorta (coeliac LNs), in the neck (cervical LNs) and in the mesentery (mesenteric LNs)
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HEVs
Sentinel Lymph Node
Lymph drains into blood and
can be route of metastasis to
other organs
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The Spleen: filters blood
• In contrast to lymph nodes, which are
inserted in the lymph circulation, the
spleen is inserted in the blood circulation.
* There are no lymphatics leading to the
spleen.
The Spleen has 2 major regions
related to it’s two different functions
• White Pulp: lymphatic
– Small arterioles surrounded by sheaths of
lymphocytes= Peri-Arteriole Lymphoid
Sheaths (PALS- human arrangement slightly
different)
– Surrounded by marginal zone
• Red Pulp: clears RBCs
– “Cords” of cells: Erythrocytes, macrophages,
dendritic cells, few lymphocytes and plasma
cells
– Also contains venous Sinusoids
Spleen- surface of a fresh cut appears
stippled due to red and white pulp
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White pulp: two components
1. PALS- T cells
• periarteriole lymphoid sheath
2. Lymphoid follicles- B cells
• spherical structures Scattered throughout PALS
• Visible to the naked eye on the surface of a freshly cut spleen as white spots.
Spleen- human
capsule
trabeculae
Red pulp
Central artery
White pulp
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Function of the spleen
• Erythrocytes enter the red pulp, push through
the masses of macrophages filling the splenic
cords and enter the sinuses.
– Macrophages engulf old rbcs and antigens in blood
• Lymphocytes are brought into the spleen by
the arteries and arterioles; they also get
dumped into the red pulp and thenenter the
marginal sinus and migrate to their respective
domains
– B cells to the follicles, T cells to the PALS
Spleen: Red Pulp and Sinusoids
Reticular fibers and endothelial cells
Spleen- Red pulp
Sinusoid
Pulp
Cord
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Spleen- Red pulp
Mucosal Immune System MALT- Mucosal Associated Lymphoid
Tissue
• Mucosal surfaces of mouth, respiratory and reproductive tracts are colonized by lymphocytes and accessory cells
• Respond to ingested, inhaled antigens
• BALT (bronchial) :
• GALT (gut) :
– Tonsils
– Peyer’s Patches
– Appendix
Tonsils
• Latin tonsa (stake set up on the shore)
• At entrance to GI tract:
– 1 pharangeal= “adenoids”
– 2 tubal
– 2 palatine= “tonsils” (from pouch 2)
– 1 lingual
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Human Tonsils
1.Palatine
2.Lingual
3.Pharyngeal
4.Tubal
Pharyngeal
Tubal
Palatine
Lingual
nodes
Pharynx Diagram of the
Tonsil • Aggregated
lymphoid follicles
• Corrugated surface with cracks and pits CRYPTS lined with stratified squamous epithelium
• become filled with sloughed off cells, dead lymphocytes and fluid
• good culture medium for bacteria
Pharynx
Plane of cross section shown in next slide
Peyer’s Patches
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Peyer’s patches in a cross section of the ileum of
the small intestine
M cell (microfold cell) in the surface of
the Peyer’s patch is the cell
specialized to uptake Ag from the gut
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Appendix
• Worm-like projection of the human large intestine, 10-15 cm long and up to 8mm in diameter.
• Dense, diffuse lymphoid tissue packed with some 200 lymphoid follicles.
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Appendix
There is a
network of
lymphatics
surrounding
each follicle
Summary
• The immune system is composed of many
cells, tissues and organs
• The anatomical arrangement of the
immune system facilitates interactions
between antigens and cells at
appropriate times
• If you understand the anatomy, you will be
able to better understand the context of
these interactions
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